ABSTRACT: With the premise that U.S. Veteran demographics reveal an aging population with significant mobility limitation and oxidative stress is tightly linked to both of these characteristics, a series of skeletal muscle/vascular studies are proposed. Specifically, in a series of recent studies our group has documented positive vascular consequences of antioxidant supplementation during exercise in older subjects that negatively impacted young people. Further provocative findings revealed that following exercise training the older subjects were now also negatively impacted by the antioxidant supplementation. These findings have implications for the understanding of the complex balance between the positive effects of exercise-based rehabilitation, exercise induced oxidative stress, aging, frailty, and subsequent mobility limitation. Therefore four specific aims are proposed that will address the following: 1) Is acute exercise-induced oxidative stress greater in muscle or blood with age? 2) Which response to muscular work generates oxidative stress with age? 3) What are the acute vascular consequences of oxidative stress with age? And 4) The role of oxidative stress in the exercise-induced vascular adaptations with age. The Central Hypothesis of this grant proposal is that oxidative stress is a key mechanism that can be manipulated to contribute to the benefits of exercise in aging humans. PUBLIC HEALTH RELEVANCE: Narrative: In the population at large it is estimated that by the year 2050 over 21% of people will be over 60 years of age, in stark contrast VA demographics reveal that 51% (12.3 million) of veterans are already over this age. Typically, with age comes inactivity and often mobility limitation. This has and will increasingly place heavy demands on the VA health care system. Additionally, vascular aging per se was recently recognized as a major risk factor for cardiovascular disease and hypertension which afflicts 30 and 60 % of veterans, respectively. The former continues to be the leading cause of death in U.S. veterans. A common, but as yet not well understood link between these processes is oxidative stress. Given the large number of older veterans and the clear link between aging, inactivity, oxidative stress, and lethal cardiovascular disorders, both aging and vascular disease have appropriately been identified as Medical Research Priorities for the VA health care system. Thus, the Central Hypothesis of this proposal that oxidative stress is a key mechanism that can be manipulated to contribute to the benefits of exercise in aging humans is highly relevant to the VA patient care mission.